SUMMARY More than 1.1 million people in the United States (US) are living with human immunodeficiency virus (HIV) infection, and an estimated 30% of people living with HIV (PLWH) have evidence of chronic kidney disease (CKD). Compared to the general population, the rate of end-stage renal disease (ESRD) among PLWH is tenfold greater and mortality on dialysis is 19-fold higher. Contributors to CKD in PLWH include comorbidities shared with the uninfected population, HIV-specific factors, and genetic variants; however, the interplay of these various determinants remains incompletely understood. Existing CKD risk prediction tools for PLWH have low sensitivity and insufficient positive predictive value for clinical decision-making. The ability to risk- stratify PLWH and distinguish those at highest risk for future development of CKD from those at low risk is critical to optimize care and patient outcomes. PLWH at high risk can be targeted for interventions to slow CKD progression and improve survival, including earlier establishment of nephrology care and referral for transplantation; while identification of those at low risk allows for the development of a living donor selection framework specific to PLWH, effectively expanding HIV+ to HIV+ transplantation to include living donors. We hypothesize that the impact of HIV on CKD risk varies by the interplay between comorbid conditions, HIV- related factors, and genetic variants, and distinct phenotypes of PLWH with high and low CKD risk exist. To better understand this relationship, we will leverage the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a unique prospective clinical cohort with > 34,000 participants, and will address the following unique aims: (1) to explore the association of unique HIV-related processes and clinical characteristics with risk for CKD; (2) to explore the association of genetic variants with risk for CKD and correlate histologic findings with genetic risk; and (3) develop a tool for predicting CKD risk among PLWH. Stratification by risk for future development of CKD is critical for identifying those PLWH at highest risk that would benefit from early nephrology care and referral for transplantation and those at lowest risk that could be eligible for living kidney donation. Using an existing cohort of PLWH representative of the US HIV population, with time varying data and DNA for genotyping, to inform CKD risk prediction is necessary, practical, and novel. Our findings will contribute new insights into the relationship between HIV and risk for kidney disease.